ABSTRACT Growing evidence from epidemiologic, clinical and animal model studies of attention-deficit/hyperactivity disorder (ADHD) supports a role for pre- and postnatal immune and infectious factors in the pathogenesis of this common, disabling and frequently persistent disorder. ADHD is a major contributor to the psychosocial and economic burden of neurodevelopmental disabilities globally, affecting 5% of children in the United States, and is frequently complicated by comorbidity with substance use and other psychiatric disorders, learning disabilities and criminality. Associations of ADHD with exposure of mothers during pregnancy and infants in early life to specific pathogens and fever episodes are reported, but individual differences in innate and adaptive immune responses, and concomitant exposures to medications and immunity-regulating micronutrients, have not been rigorously and prospectively addressed. This project will leverage the unique data and biological sample resources of the Norwegian Mother and Child Cohort Study (MoBa) and the Center for Infection and Immunity at Columbia University for insights into the role of infection and immunity in ADHD through pursuit of three complementary aims that address not only maternally-reported infection, fever and immune/inflammatory disease but also quantitative measures of immune activation and pathogen-directed antibody responses. Because MoBa mothers report illness events and symptoms as well as medication use in 4-week intervals throughout pregnancy, unusually rich information is available to relate the timing of these phenomena, rather than gestation per se, to ADHD outcomes. In Aim 1 we will investigate the relationship of maternal and child infection, fever and immune disorders to ADHD risk using prospective MoBa questionnaire data, controlling for medication use (antipyretics, analgesics, antibiotics) and intake of micronutrients with immunomodulatory potential (vitamin D, zinc). In Aim 2 we will define the immune signatures in plasma from mothers and children during pregnancy and at birth and determine their association with ADHD risk using multiplexed immunoassays (Luminex) to compare levels of 60 immune/inflammatory molecules with known or suspected effects on neurogenesis and synaptogenesis broadly as well as ADHD-relevant dopaminergic circuitry more specifically. In Aim 3 we will examine the role of specific infectious agents implicated in ADHD by measuring maternal antibodies at mid-gestation and birth to ToRCH pathogens Toxoplasma gondii, rubellavirus, cytomegalovirus and herpes simplex viruses 1 and 2 using multiplexed immunoassays (Luminex) and to influenza viruses using luciferase immunoprecipitation systems (LIPS). In concert, these aims have the potential to identify novel factors and biomarkers for ADHD risk that could facilitate early diagnosis and intervention and guide the development of preventive measures.